The field of histone deacetylation continues to receive considerable interest due to the ability of histone deacetylase (HDAC) inhibitors to modulate transcriptional activity. Molecules from this therapeutic class have the potential to occupy an indomitable position in the fast-moving cytostatic market. One reason why HDAC inhibitors could play such a key role in this $2 billion market is that they are able to improve the efficacy of existing cytostatics (such as the retinoids - for a review click here). Moreover, for the first time, they are able to target the transcription of specific disease-causing genes, improving the therapeutic window of cancer therapies. More recently, HDAC inhibitors have been linked to other indications such as autoimmune disorders (click here). In response to the emergence of HDAC inhibitors as a major therapeutic class LeadDiscovery recently published one of the most comprehensive overview of the pharmaceutical potential of HDAC inhibitors (click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer").

At the time of this report suberoylanilide hydroxamic acid (SAHA) was one of the most advanced candidate inhibitors. Key clinical data on SAHA was highlighted in our previous edition of TherapeuticAdvances. In this edition we report important data regarding Novartis’ new HDAC candidate, NVP-LAQ824.

The development of NVP-LAQ824 by a group led by Peter Atadja at Novartis (J Med Chem. 2003 Oct 9;46(21):4609-24) was based on the proposition that HDAC inhibitors should be composed of a zinc ligand coupled to a “specificity element” by a spacer. Several structural classes that met this model were identified through HTS of Novartis’ chemistry library. Identification of the hit, NVP-LAK974, and subsequent optimization produced NVP-LAQ824. This molecule inhibited HDAC activity with an IC50 of 32nM and proliferation of cancer cell lines with IC50s of 10-150nM. The anti-proliferative potency is up to 200-fold greater than that of SAHA. In vivo, NVP-LAQ824 almost completely blocked the growth of both human colon and lung cancer xenografts at tolerable doses. Ongoing studies are being conducted to determine the HDAC isoform specificity of NVP-LAQ824 and clinical trials have also been initiated in patients with solid tumors or leukemia.

Entry date Monday, November 17, 2003

Adapted from Remiszewski et al, J Med Chem. 2003 Oct 9;46(21):4609-24.